Synthesis of (dibromocyclobuta) aromatic compounds

ABSTRACT

A method for the synthesis of cyclobuta aromatic compounds by cyclizing two ortho dibromoalkyl substituents is described. Using a mediator, such as nickel metal, and continuous removal of product from contact with the mediator, high product yields are achieved. A method for bromination of ortho alkyl substituents of aromatic compounds is also described.

FIELD OF THE INVENTION

The present invention is directed to methods for the synthesis of(dibromocyclobuta) aromatic compounds, and more particularly to a highyield method of synthesizing bis (dibromocyclobuta) aromatic compounds.

BACKGROUND OF THE INVENTION

Polyacenes are polymers predicted to show industrially importantproperties including non-linear optics and high-temperaturesuperconductivity, see references 1. Unfortunately, confirmation of thepredicted properties has not yet been performed due to the lack of anefficient method to prepare polyacenes.

Cyclobutabenzenes, especially the 7,8-dibromo derivatives 2 (depicted inscheme 1), are valuable synthons for functionalized ortho-quiodimethanesthat can be trapped by Diels-Alder reactions. The product of such areaction is a tetrahydronaphtalene 4 derivative having two cis bromineatoms in the 1 and 4 positions. If the dienophile has two cis hydrogenatoms, and since the Diels-Alder addition is completely endo, thesehydrogen atoms end the reaction antiperiplanar to the bromine atoms.Such an orientation facilitates elimination of two HBr molecules to formthe corresponding naphtalenic system 6 as described in reference 2 anddepicted in scheme 1:

Reference 4 discloses the Diels-Alder condensation of7,8,9,10-tetrabromo-[1,2][4,5] bicyclobutabenzene 16 withtetracyanoethylene 18, scheme 2:

Reference 4 further discloses the Diels-Alder condensation of twoequivalents of 7,8-dibromo cyclobutabenzene 2 with one equivalent of1,4-benzoquinone 12 to form the bis-adduct that eliminates fourequivalents of HBr to form the pentacyclic quinone 14, scheme 3:

Thus, it is expected that of 7,8,9,10-tetrabromo-[1,2][4,5]bicyclobutabenzene 16 can react with benzoquinone 12, in analogy toschemes 2 and 3, to form polyquinone 20, scheme 4:

As further seen in scheme 4, subsequent reduction of polyquinone 20 isexpected to yield polyacene 22.

As the use of non-brominated bicyclobutabenzene would result in twosaturated centers between the aromatic and quinone moieties,deconjugating the polyacene 20, to synthesize polyquinone 20 it isnecessary to use the brominated bicyclobutabenzene, compound 16 or anyof the four all-trans tetrabromo isomers thereof. For the Diels-Aldercondensation to take place, two bromine atoms on a cyclobutane ring mustbe in a trans orientation.

A number of methods for synthesizing compound 16 or any of the fourall-trans bromo isomers thereof have been disclosed. Reference 5discloses a synthesis of compound 16 using iodide-mediated ring closureand reports a 2% yield. Reference 4 describes a synthesis of compound 16using stochiometric amounts of (Bu₃P)₂Ni(COD) and reports a 10% yield.

The bottleneck of the above-proposed route of synthesizing polyacenessuch as 22 is the preparation of compounds such as 16. The known methodsof synthesizing compound such as 16 suffer from low yields.

It would be highly advantageous to have a high-yield synthesis for(trans dibromocyclobuta) aromatic compounds such as 16.

REFERENCES

-   1. a. Kivelson, S.; Chapman, O. L. Phys. Rev. 1993, b28, 7326.    -   b. Tanaka, K.; Ohzeki, K.; Yata. S. Synth. Metals 1984, 9, 41.    -   c. Ozaki, M. Ikedo, Y.; Nagoya, I. Synth. Metals 1989,28 C801.-   2. Stanger, A.; Askenazi, N.; Shachter, A.; Blaser, D.; Stellberg,    P.; Boese, R. J. Org. Chem. 1996, 61, 2549.-   3. Stanger, A.; Askenazi, N.; Boese, R.; Blaser, D.; Stellberg, P.;    Chem. Eur. J. 1997, 3, 208.-   4. a. Stanger, A.; Shachter, A.; Askenazi, N.; Boese, R. and    Stellberg, P. “Nickel Mediated Cyclobutabenzenes Syntheses” in    Organic Synthesis via Organometallics OSM 5, Helmchen, G.; Dibo J.;    Flubacher, D.; Wiese, B.: Eds. Friedrich Vieweg & Sohn Verlags GmbH,    Braunschweig/Wiesbaden, 1997, pp. 59–66.    -   b. Shachter, A. “Cyclobutabenzenes: An Entry to a New Synthetic        Methodology” D.Sc Thesis, Technion, Haifa, Israel, 1997.-   5. Sheferd, M. K. J. Chem. Soc. Perkin Trans I 1988, 961.

SUMMARY OF THE INVENTION

The present invention is directed to a method for the synthesis of a(dibromocyclobuta) aromatic compound by cyclicizing two orthodibromomethyl substituents of an aromatic moiety. In the product, abromine atom of an individual cyclobutyl ring is predominantly trans tothe other bromine atom of the same cyclobutyl ring.

The method of the present invention is exceptionally suitable forsynthesizing aromatic compounds substituted with multipledibromocyclobutane rings, especially when the substrate includes a1,2,3,4 or 1,2,4,5 tetra (dibromomethyl) aromatic ring.

Reference 3 describes a nickel-mediated synthesis for the synthesis ofhexabromo-tricyclobutabenzene 8, scheme 5:

However, under the conditions of scheme 5, hexabromo-tricyclobutabenzene8 undergoes butyl ring opening to yield hexabromo-hexaradialene 10, sothat the final yield of the reaction is 35% compound 8 and 30% compound10. In the analogous reaction (not depicted) using 1,2,4,5-tetradibromomethyl benzene to produce compound 16, only an 8% yield ofcompound 16 is achieved.

While not wishing to be held to any one theory, it is likely that thelow yield of compound 16 using a reaction analogous to that depicted inscheme 5 is a result of decomposition of compound 16 by contact with thenickel mediator, probably to an undefined polymeric material. Bymodifying the nickel-mediated synthesis described in scheme 5 so as toremove compound 16 formed before decomposition, the method of thepresent invention provides for an efficient method of producing a(dibromocyclobuta) aromatic compound.

There is provided according to the teachings of the present invention amethod for the preparation of an aromatic product having at least onedibromocyclobuta substituent wherein two bromine atoms of an individualcyclobutane ring are in a trans orientation, by dissolving a substratehaving an aromatic moiety with at least two ortho dibromomethylsubstituents in a reaction solvent (preferably containing DMF). Thedissolved substrate is brought in contact with a mediator (preferablynickel, especially as nickel metal powder). Subsequent to cyclization,contact of a cyclicized product with the mediator is limited to preventproduct decomposition.

The cyclization reaction is preferably performed at an elevatedtemperature.

According to a feature of the present invention, limiting the contact ofthe cyclicized product with the mediator is achieved by using acontinuous flow of solvated substrate through a reaction vessel, such asa column, containing substantially immobilized mediator.

According to an additional feature of the present invention, limitingthe contact of the cyclicized product with the mediator is achieved byusing a two-phase solvent. The first phase is the reaction solvent andthe second phase is an extraction solvent, where the cyclicized productis more soluble in the extraction solvent than the substrate is.Preferably the extraction solvent is a mixture of one or more apolarsolvents such as straight chain, branched or cyclic alkyl solvents,petrol ethers, hexane, cyclohexane, heptane, methylcyclohexane, octane,nonane, decane, decalin and the such.

Preferably, throughout the reaction, product-containing extractionsolvent is removed and replenished from the reaction vessel.

According to the teachings of the present invention there is provided amethod for the preparation of a compounds of the general formula:

wherein two bromine atoms of an individual cyclobutane ring are in atrans orientation according to the method described hereinabove, whereinthe substrate is

and where R₁, R₂, R₃, R₄, R₅, and R are independently selected from agroup consisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone and especiallywhere R₃, R₄, R₅, and R₆ are hydrogen atoms.

According to the teachings of the present invention there is alsoprovided a method for the preparation of compounds of the generalformula:

wherein two bromine atoms of an individual cyclobutane ring are in atrans orientation according to the method described hereinabove, whereinthe substrate is

and where R₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from agroup consisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone and especiallywhere R₃, R₄, R₅, and R₆ are hydrogen atoms.

In the reactions of the present invention described above, it is clearto one skilled in the art that since predominately the trans isomer ofthe dibromocyclobuta substituent result, then depending on the symmetryof the substrate a mixture of three or four isomers results. The art ofseparation of the various isomers from a mixture resulting from thepresent invention is known to one skilled in the art.

The cyclization reaction of the present invention described hereinaboverequires an ortho bis(dibromomethyl) aromatic substrate. Thus, themethod of the present invention further includes a method of brominationof alkyl groups (especially methyl groups) attached to aromatic moieties(especially benzene derivatives). The method is based on the irradiationwith light of an alkyl-substituted aromatic compound in the presence ofmolecular bromine. Unlike the methods known in the art, the presentmethod is based on performing the reaction in a chloroform-containingsolvent.

Thus, there is also provided according to the teachings of the presentinvention a method of bromination by dissolving a substrate having analkyl substituent on an aromatic moiety in a chloroform-containingsolvent. The dissolved substrate is heated (preferably to the boilingpoint under reflux conditions) and irradiated with electromagneticradiation (preferably visible light, and more preferably light includinga wavelength that leads to the production of bromine radicals).

The bromination method of the present invention is exceptionally suitedfor the dibromination of methyl substituents of aromatic moieties toyield the dibromomethyl substituent. The bromination method of thepresent invention is even more exceptionally suited for thetetrabromination of ortho dimethyl substituents of aromatic moieties toyield the α, α, α′, α′-tetrabromo-ortho-xylene moiety.

According to the teachings of the present invention, there is provided amethod as described hereinabove for the preparation of a compound of thegeneral formula:

wherein R₁ and R₂ are independently selected from a group consisting ofhydrogen, halogen, straight alkyl, branched alkyl, cycloalkyl,substituted alkyl, alkyl aryl, aryl, substituted aryl, heterocyclealkenyl, cycloalkenyl, ether, thioether, amide, amine, alcohol, nitro,thioester, ester, aldehyde and ketone;and wherein R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, fluorine, chlorine, iodine, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone, andespecially where R₃, R₄, R₅, and R₆ are hydrogen atoms.

Specifically, the present invention provides a method of brominating1,2,4,5-tetramethylbenzene (durene) to yield 1,2,4,5-tetra(dibromomethyl) benzene as well as a method of brominating 1,2,3,4-tetramethylbenzene to yield 1,2,3,4-tetra (dibromomethyl) benzene, a compounduseful for producing [1,2][3,4]tetrabromo bicyclobutabenzene. Clearly,the present invention provides a method for bromination of thederivatives of 1,2,4,5-tetra methylbenzene and 1,2,3,4-tetra(dibromomethyl) benzene to yield the respective brominated derivativesof 1,2,4,5-tetra (dibromomethyl) benzene and [1,2][3,4] tetrabromobicyclobutabenzene.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings, wherein:

FIG. 1 is of a device useful in implementing the first embodiment of thepresent invention;

FIG. 2 is of a device also useful in implementing the first embodimentof the present invention; and

FIG. 3 is of a device useful in implementing the second embodiment ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is of a method for the synthesis of a(dibromocyclobuta) aromatic compound by cyclicizing an aromatic compoundhaving two ortho dibromomethyl substituents. In the product, a bromineatom of an individual cyclobutyl ring is predominantly trans to theother bromine atom of the same cyclobutyl ring.

The principles of the synthesis of the present invention may be betterunderstood with reference to the drawings, the accompanying descriptionand the examples hereinbelow. Two specific embodiments of thecyclization of the present invention are discussed in detailhereinbelow: using a two-phase solvent or using a continuous flow ofsubstrate through a column-immobilized mediator. It should not beconstrued that the present invention be limited by the specific chemicalreactions and conditions listed.

It is important to note that, as described hereinabove, the method ofthe present is specifically directed at cyclization of tetra(dibromomethyl) benzenes to yield tricyclic systems. The innovativeconditions of the present invention yield only small amounts of theincompletely cyclicized bis (dibromomethyl) cyclobutyl benzene product.

The method of the present invention as discussed herein specificallyrelates to the cyclization of tetra (dibromomethyl) benzenes, as this isa class of compounds where double cyclization is exceptionallydifficult. It is clear to one skilled in the art, however, that themethod of the present invention can be applied to the cyclization of anyaromatic compound having two ortho dibromomethyl substituents. Methodsof cyclization known in the art give a substrate-dependent yield ofbetween 38% and 85%. It is expected that for any given substrate themethod of the present invention will give a significantly improved yieldwhen compared to the yields of prior art methods.

Cyclization of ortho bis(dibromomethyl) aromatic compounds using amulti-phase solvent system

According to the first embodiment of the present invention, thesubstrate (an ortho bis (dibromomethyl) aromatic compound) and amediator are placed in a reaction vessel with a reaction solvent. Anextraction solvent is added to the reaction vessel. The reaction mixtureis agitated and heated so as to allow cyclization of the substrate. Oncecyclization occurs and the product is formed, due to solubilityconsiderations the product enters the extraction solvent and is nolonger in contact with the mediator, preventing subsequentdecomposition. Methods of isolation and purification of the product fromthe extraction solvent are well known to one skilled in the art.

Specifically the first embodiment of the present invention includesusing nickel, especially in the form of nickel metal powder as amediator and preferably at least about 0.5 equivalents of mediator tosubstrate, more preferably at least about 1 equivalents of mediator tosubstrate, even more preferably at least about 2 equivalents of mediatorto substrate, and most preferably at least about 5 equivalents ofmediator to substrate.

Any starting concentration (M) of starting material in the reactionsolvent can be used, but more often

between 0.01 and 2, preferably between 0.01 and 1, more preferablybetween 0.01 and 0.5,   even more preferably between 0.02 and 0.2,   andmost preferably between 0.07 and 0.1.

Generally, the substrate of the present invention is soluble in polarsolvents such as DMF (dimethylformamide) but only slightly soluble innon-polar solvents. Although not wishing to be held to any one theory,it is believed that the DMF acts as a ligand to stabilize reactiveorganometallic intermediates (such as a mediator-substrate complex).

It is important to note that using the method of the present invention,the brominated substrate needs not be soluble in the reaction solvent.Although not wishing to be held to any one theory, it is believed thatin cases when the substrate is only barely or not soluble in thereaction solvent, the DMF acts to solubilize the reactive organometallicintermediates (such as a mediator-substrate complex). In cases where thesubstrate is not soluble in the reaction solvent, the amount ofsubstrate above is calculated as actual and not as concentrations, as isclear to one skilled in the art.

Thus, it is desirable that the reaction solvent is any solvent ormixture of solvents containing DMF. Preferably the reaction solvent isso composed that at the beginning of the reaction there are at least 2equivalents DMF for every equivalent substrate; more preferably thereare at least 10 equivalents DMF for every equivalent substrate; evenmore preferably there are at least 25 equivalents DMF for everyequivalent substrate and most preferably there are at least 50equivalents DMF for every equivalent substrate. If other factors allow,substantially neat DMF can be used as a reaction solvent of the presentinvention. It is important to note that, generally speaking, the rate ofreaction is faster with an increasing DMF component in the reactionsolvent.

It is obvious to one skilled in the art that it is ideal that thesubstrate be barely or not at all soluble in the extraction solvent. Itis equally obvious to one skilled in the art that it is alsoadvantageous that the product be slightly or not all soluble in thereaction solvent.

As is clear to one skilled in the art, the greater the solubility of theproduct in the extraction solvent and the lesser the solubility of theproduct in the reaction solvent the greater the ultimate yield shall be.Thus ideally: 1) the product is at least slightly soluble, andpreferably soluble in the extraction solvent 2) the substrate issubstantially insoluble in the extraction solvent 3) the reactionsolvent and extraction solvent are substantially immiscible or at leastproduce a two-phase solvent system.

Despite this, the choice of solvents is not unlimited and each set ofsubstrate and product have different solubility characteristics.Therefore, the minimal requirement of the first embodiment of thepresent invention to get a reasonable yield is that the extractionsolvent is any solvent or mixture of solvents that upon mixing with thereaction solvent yields a solvent system having at least two-phases, anextraction phase and reaction phase, so that the product is at leastsomewhat soluble in the extraction phase. In such a “minimal” case it ispossible to remove product-containing extraction phase from the reactionvessel and to replenish it with fresh extraction solvent. When freshextraction solvent is added to the reaction, even if the product is lesssoluble in the extraction phase than in the reaction phase, there is apartition of the product between the two solvent phases. Even if asignificant proportion of the product remains in the reaction phase, bycontinuously removing product-containing extraction phase and addingfresh extraction solvent, product is continuously removed from thereaction even if the product is only slightly soluble in the extractionphase.

Considering the nature of the expected products, a mixture of one ormore apolar solvents such as straight chain, branched or cyclic alkylsolvents, petrol ethers, hexane, cyclohexane, heptane,methylcyclohexane, octane, nonane, decane, decalin and the such arepreferred-components of an extraction solvent of the present invention.

The reaction temperature can be between 40° and 150° C., preferablybetween 50° and 120° C., more preferably between 60° and 100° C., evenmore preferably between 70° and 90° C., and most preferably between 75°and 85° C. As is clear to one skilled in the art, it is preferable thatthe reaction temperature be lower than the boiling points of both theextraction and the reaction solvents. In the case where it is chosen touse a temperature that is somewhat higher than the boiling point of oneof the two solvents, a reflux apparatus can be used to allowcondensation and recovery of the evaporated solvents. Due to the factthat when the reaction solvent boils mixing is too vigorous, it ispreferable that the reaction temperature be always lower than theboiling point of the reaction solvent.

As is clear to one skilled in the art, the reaction of the presentinvention can also be performed in a closed system at elevatedpressures.

It is necessary to ensure that the mediator-is in effective contact withthe reaction solvent and that there be sufficient contact between thereaction solvent and the extraction solvent to allow efficient transferof cyclicized product from the reaction solvent to the extractionsolvent. On the other hand, it is necessary to minimize contact ofproduct-containing extraction solvent with the mediator. Thus, theintensity of agitation, whether thermal or mechanical, needs to beregulated with the aforementioned factors in mind.

As noted above, for the reaction yield be maximal, it is preferred thatproduct-containing extraction phase be removed from the reaction vesselduring the reaction, preferably continuously removed. When theproduct-containing extraction phase is removed from the reaction vesselduring the reaction, it is preferable to concurrently replenish theextraction phase by adding a substantially equal amount of freshextraction solvent.

It is preferable that the extraction solvent be less dense then thereaction solvent, so that product containing extraction solvent can beeasily collected from the top of the reaction vessel withoutinterference from mediator which tends to collect at the bottom of thereaction vessel.

In FIG. 1, a reaction vessel 10 useful for implementing the firstembodiment of the method of the present invention is depicted. Reactionsolvent 12 (DMF) is denser than extraction solvent 14 (heptane). Due toits density, a mediator powder 16 remains in reaction solvent 12.Mechanical stirrer 18 causes sufficient agitation to prevent settling ofmediator powder 16 at the bottom of vessel 10, ensuring contact betweenmediator powder 16 and substrate dissolved in reaction solvent 12.Additional extraction solvent is continuously added through feed tube20. The addition of extraction solvent through feed tube 20 causes acontinuous overflow of product-containing extraction solvent throughport 22. Overflow is collected for subsequent product isolation. Heatingis provided by oil bath 24.

It is also possible to implement the first embodiment of the presentinvention when the extraction solvent is denser then the reactionsolvent, the excess extraction solvent is collected from the bottom ofthe reaction vessel. In such a case care is taken to prevent insolublematerial such as the mediator from being removed from the reaction alongwith the product.

In FIG. 2, a reaction vessel 26 useful for implementing the firstembodiment of the method of the present invention is depicted. Reactionsolvent 12 is less dense than extraction solvent 14. Due to the presenceof a porous sintered glass layer 28 mediator powder 16 remains inreaction solvent 12 although reaction solvent can freely flow throughglass layer 28 to make contact with extraction solvent 14. Mechanicalstirrer 18 causes sufficient agitation to prevent settling of mediatorpowder 16 on glass layer 28, ensuring contact between mediator powder 16and substrate dissolved in reaction solvent 12. Product containingextraction solvent 14 is continuously drained through port 22.Additional extraction solvent is continuously added through feed tube 20to maintain a sufficient amount of solvent in vessel 26.

Cyclization of ortho bis(dibromomethyl)aromatic Compounds UsingContinuous-Flow Through Column-Immobilized Mediator

According to the second embodiment of the present invention, thesubstrate (an ortho bis(dibromomethyl) aromatic compound), dissolved ina reaction solvent, is streamed through a column (or functionallyequivalent device) containing an immobilized mediator, preferablynickel, especially as nickel metal powder. As the substrate flowsthrough the column, contact of substrate with the mediator leads toformation of the desired product. Preferably the column is heated toallow efficient cyclization of the substrate. Clearly, theinterdependence of the reaction conditions, such as the exact nature ofthe reaction solvent, the flow rate of flow, the condition of themediator the nature of the substrate, the length of the column and thetemperature necessitates optimization of every specific reaction. As isclear to one skilled in the art, optimization involves identifying a setof conditions that lead to maximal product formation yet minimal productcontact with the mediator.

Specifically the second embodiment of the present invention includesusing any starting concentration (M) of starting material in thereaction solvent, but more often

between 0.01 and 2, preferably between 0.01 and 1, more preferablybetween 0.01 and 0.5,   even more preferably between 0.02 and 0.2,   andmost preferably between 0.05 and 0.08.

The reaction solvent chosen is as specified hereinabove for the firstembodiment of the present invention.

The rate of flow of reaction solvent through the reaction column can beanything, but more often (in units of seconds to pass one column-volumeof solvent)

between 1 and 560, preferably between 5 and 240, more preferably between10 and 120, even more preferably between 15 and  45, and most preferablybetween 18 and 22.

The reaction temperature can be between 40° and 160° C., preferablybetween 80° and 160° C., more preferably between 100° and 140° C., evenmore preferably between 110° and 130° C., and most preferably between115° and 125° C.

Methods of isolation and purification of the product from theproduct-containing reaction solvent collected from the terminal end ofthe column is clear to one skilled in the art.

A column 30, suitable for realizing the second embodiment of the presentinvention is depicted in FIG. 3. Substrate containing reaction solventis introduced through inlet 32 of column 30. As the reaction solventflows through column 30, substrate reacts to yield product according tothe method of the present invention by interaction with immobilizedmediator powder 34. In FIG. 3, mediator powder 34 is immobilized inglass wool. Product-containing solvent drips out through stopcock 36 andis collected. Column 30 is jacketed, allowing heating of solvent insidecolumn 30 by the introduction of a heated liquid through port 38.

Bromination of Alkyl Groups Attached to Aromatic Compounds

Most generally, bromination according to the method of the presentinvention is a light-catalyzed bromination of alkyl groups attached toan aromatic substrate dissolved in chloroform at reflux by addition ofmolecular bromine.

An aromatic compound with at least one alkyl group is dissolved inchloroform and placed in a reaction vessel configured so as to allowreflux of the solution. The solution is allowed to reflux and irradiatedwith light; Br₂ is added in portions to the refluxing chloroformsolution. After the reaction is complete, reflux and irradiation arestopped and the brominated product isolated from the chloroform.

Preferably, sunlight or a sunlight lamp is used to irradiate thereaction mixture. More preferably, light containing a wavelengthsufficient to produce bromine radicals is used.

The starting concentration (M) of starting material in the chloroformsolvent can be anything, but more often

between 0.01 and 2, preferably between 0.01 and 1, more preferablybetween 0.01 and 0.5,   even more preferably between 0.02 and 0.2,   andmost preferably between 0.07 and 0.1.

Isolation and purification of the product can be performed using any ofthe methods known to one skilled in the art.

It is important to note that in the art, for example, a 76% yield of1,2,4,5-tetra (dibromomethyl) benzene can be achieved by reacting dureneunder similar conditions using CCl₄ as a reaction solvent. Unexpectedlyand unpredictably, a 96% yield is achieved using the method of thepresent invention that is using chloroform as a solvent.

SPECIFIC SYNTHETIC EXAMPLES

Bromination of Durene to Yield Octabromodurene

Br₂ (46.6 ml, 0.907 mole) was added dropwise to a refluxing solution ofdurene (2.964 gr., 0.022 mol) in chloroform (220 ml). The heat and lightneeded for the reaction were supplied by a 375 W sunlight lamp. The endof the reaction (after about 5 days) was determined by ¹H NMR. Thereaction mixture was cooled to room temperature and neutralized with a5% aqueous NaHCO₃ solution. The solid product was filtered, washed witha 10% thiosulphate solution, water and methanol. After the methanol washthe product was dried in high vacuum until constant weight achieved.Obtained were 16.095 gr. (96% yield) of octabromodurene.Cyclization of Octabromodurene

Example A Two-Phase Solvent

Metallic nickel powder (1.157 gr., 0.0197 mol), octabromodurene (1.507gr., 1.969 mmol) and DMF (26 ml) were placed in a 50 mol reactionvessel. Heptane was added to fill the vessel. The reaction mixture washeated to 80° C. and additional heptane was introduced using a syringepump at a rate of 10 ml/hour. The heptane overflow was collected. DMFwas added from time to time to compensate for its loss as under thesemi-improvised conditions used some DMF “escaped” to the heptane phase.After 9 days the collected heptane phase was evaporated using vacuum. Anamount of chloroform sufficient to dissolve the product-containingresidue was added and adsorbed, onto 1 gram Florisil® (60–100 meshactivated magnesium silicate, CAS nr. 1343-88-0) and chloroform removedunder vacuum. The product adsorbed on the Florisil® was placed on top ofan open topped Florisil®-packed chromatographic column and eluted usingchloroform. The chloroform solution was washed with 5% HCl, 5% NaHCO₃,water, and dried over MgSO₄. A 22% yield of [1,2][4,5] tetrabromobicyclobutabenzene 16 was obtained.)

Example B Immobilized Nickel

Metallic nickel powder (6.5 gr.) spread on glass wool was placed in ajacketed column (10 mm internal diameter) so that the height of thenickel on glass wool was 5 cm. The column was heated to 120° C., and asolution of octabromodurene (1.54 gr., 2 mmol) in warm DMF (32 ml) wasallowed to pass through the column at a rate of 1 drop/sec. After allthe octabromodurene solution was added, neat EMT was introduced into thecolumn at a rate of 1 drop/sec until the solution dripping from thecolumn was colorless. The total amount DMF added was approximately 70ml. The DMF was evaporated and the product isolated as described inExample A. A 28% yield of tetrabromo bicyclobutabenzene 16 was obtained.Bromination of 1.2,3,4-tetramethyl Benzene to Yield 1.2.3.4-tetra(Dibromomethyl) BenzeneBr₂ (46.6 ml, 0.907 mol) is added dropwise to a refluxed solution of1,2,3,4-tetramethylbenzene (2.964 gr., 0.022 mol) in chloroform (220ml). The heat and light needed for the reaction are supplied by a 375 Wsunlight lamp. The end of the reaction is determined by ¹H NMR. Thereaction mixture is cooled to room temperature, and then neutralizedusing a 5% aqueous HaHCO₃ solution. The solid product is filtered,washed with 10% thiosulphate solution, water and methanol, and dried inhigh vacuum until constant weight achieved. Obtained is 1,2,3,4-tetrakisdibromomethyl benzene.Cyclization of Octabromo 1,2,3,4-tetramethylbenzene

Example C Two-Phase Solvent

Metallic nickel powder (1.157 gr., 0.0197 mol), tetrakis(dibromomethyl)benzene (1.507 gr., 1.969 mmol) and DMF (26 ml) are placed in a 50 mlreaction vessel and heptane is added to fill the vessel. The reactionmixture is heated to 80° C. and heptane is introduced by a syringe pumpat a 2–10 ml/hour rate. The overflow is collected.

Some DMF is added from time to time to compensate for loss of DMF to theheptane phase. The collected heptane is evaporated in vacuum. Chloroformand Florisil® are added to the residue, and dried in vacuum. The productadsorbed on the Florisil® is placed on top of an open toppedFlorisil®-packed chromatographic column, and the product eluted withchloroform. The chloroform solution is washed with 5% HCl, 5% NaHCO₃,water, and dried over MgSO₄. Obtained is tetrabromo [1,2][3,43]bicyclobutabenzene.

Example D Immobilized Nickel

Metallic nickel powder (6.5 gr.) spread on glass wool is placed in ajacketed column (10 mm internal diameter) so that the height of thenickel on glass wool is 5 cm. The column is heated to 120° C., and asolution of tetrakis(dibromomethyl)benzene (1.54 gr., 2 mmol) in warmDMF (32 ml) is allowed to pass through the column in the rate of 1drop/sec. The column is washed with DMF until the solution dripping fromthe column is colorless. The DMF is evaporated and the product worked upas described in Example C. Obtained is tetrabromo-[1,2][3,4]bicyclobutabenzene.

1. A method for the preparation of a product, the product being anaromatic compound with at least one dibromocyclobuta substituent, themethod comprising: a. providing a substrate having an aromatic moietyincluding at least two ortho dibromomethyl substituents; b. dissolvingsaid substrate in a reaction solvent to produce a dissolved substrate;c. providing a mediator; d. bringing said dissolved substrate in contactwith said mediator, in a reaction mixture, to mediate a cyclizationreaction; and e. selectively reducing contact of the product, producedby said cyclization reaction, with said mediator, in said reactionmixture.
 2. The method of claim 1 wherein said mediator includes nickel.3. The method of claim 2 wherein said mediator includes nickel metalpowder.
 4. The method of claim 1 wherein said aromatic moiety of saidsubstrate includes at least four dibromomethyl substituents, each one ofsaid at least four dibromomethyl substituents being ortho to at leastone other of said at least four dibromomethyl substituents.
 5. Themethod of claim 1 wherein said reaction solvent includes DMF (dimethylformamide).
 6. The method of claim 5 wherein said reaction solventincludes at least about 2 equivalents of said DMF for every 1 equivalentof said substrate.
 7. The method of claim 6 wherein said reactionsolvent includes at least about 10 equivalents of said DMF for every 1equivalent of said substrate.
 8. The method of claim 7 wherein saidreaction solvent includes at least about 25 equivalents of said DMF forevery 1 equivalent of said substrate.
 9. The method of claim 8 whereinsaid reaction solvent includes at least about 50 equivalents of said DMFfor every 1 equivalent of said substrate.
 10. The method of claim 5wherein said reaction solvent is substantially neat DMF.
 11. The methodof claim 1 wherein said limiting of subsequent contact includessubstantially immobilizing said mediator in a reaction vessel andbringing said dissolved substrate in temporary contact with saidimmobilized mediator by flowing said dissolved substrate through saidmediator in said reaction vessel.
 12. The method of claim 11, wherein atemperature of said reaction solvent in said reaction vessel is between40° and 160° C.
 13. The method of claim 12 wherein said temperature isbetween 80° C. and 160° C.
 14. The method of claim 13 wherein saidtemperature is between 100° C. and 140° C.
 15. The method of claim 11wherein a starting concentration of said substrate in said reactionsolvent is between 0.01 M and 2 M.
 16. The method of claim 15 wherein astarting concentration of said substrate in said reaction solvent isbetween 0.01 M and 1 M.
 17. The method of claim 16 wherein a startingconcentration of said substrate in said reaction solvent is between 0.01M and 0.5 M.
 18. The method of claim 17 wherein a starting concentrationof said substrate in said reaction solvent is between 0.02 M and 0.2 M.19. The method of claim 17 wherein a starting concentration of saidsubstrate in said reaction solvent is between 0.05 M and 0.08 M.
 20. Themethod of claim 1 wherein said reducing of said contact includesperforming said cyclization reaction in a presence of an extractionsolvent in said reaction mixture, said extraction solvent selected sothat upon mixing of said extraction solvent and said reaction solvent, asolvent system having at least two co-existing phases, a first reactionphase and a second extraction phase, is formed, such that the product isat least slightly soluble in said second extraction phase.
 21. Themethod of claim 20 wherein said reducing of said contact furtherincludes removing a portion of said second extraction phase containingthe product from said solvent system.
 22. The method of claim 21 whereinsaid reducing of said contact further includes adding fresh extractionsolvent to said solvent system so as to compensate for said removing ofsaid portion of said product-containing second extraction phase.
 23. Themethod of claim 22 wherein said removing is continuous.
 24. The methodof claim 20 wherein said extraction solvent is less dense than saidreaction solvent.
 25. The method of claim 20 wherein said extractionsolvent includes a mixture of individual solvents.
 26. The method ofclaim 20 wherein said extraction solvent includes at least one apolarsolvent.
 27. The method of claim 26 wherein said extraction solventincludes at least one of the apolar solvents from the group consistingof straight chain alkanes, branched alkanes, cyclic alkanes, petrolethers, hexane, cyclohexane, heptane, methylcyclohexane, octane, nonane,decane and decalin.
 28. The method of claim 20 wherein said extractionsolvent is further selected so as to be substantially immiscible withsaid reaction solvent and wherein said substrate is substantiallyinsoluble in said extraction solvent.
 29. The method of claim 20,wherein a temperature of said reaction phase is between 40° C. and 150°C.
 30. The method of claim 29 wherein said temperature is between 50° C.and 120° C.
 31. The method of claim 30 wherein said temperature isbetween 60° C. and 100° C.
 32. The method of claim 30 wherein saidtemperature is between 70° C. and 90° C.
 33. The method of claim 32wherein said temperature is between 75° C. and 85° C.
 34. The method ofclaim 20, wherein a temperature of said first reaction phase issubstantially a boiling temperature of said second extraction phase. 35.The method of claim 20, wherein a temperature of said first reactionphase is substantially a boiling temperature of said first reactionphase.
 36. The method of claim 20 wherein at a start of said reactionthere is at least about 0.5 equivalents mediator relative to saidsubstrate.
 37. The method of claim 20 wherein at a start of saidreaction there is at least about 1 equivalents mediator relative to saidsubstrate.
 38. The method of claim 20 wherein at a start of saidreaction there is at least about 2 equivalents mediator relative to saidsubstrate.
 39. The method of claim 20 wherein at a start of saidreaction there is at least about 5 equivalents mediator relative to saidsubstrate.
 40. The method of claim 20 wherein a starting concentrationof said substrate in said first reaction phase is between 0.01 M and 2M.
 41. The method of claim 20 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.01 M and 1 M. 42.The method of claim 20 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.01 M and 0.5 M. 43.The method of claim 20 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.02 M and 0.2 M. 44.The method of claim 20 wherein a starting concentration of saidsubstrate in said first reaction phase is between 0.07 M and 0.1 M. 45.A method for the preparation of a compound of the formula

according to claim 1, wherein two bromine atoms of an individualcyclobutane ring are in a trans orientation, according to the method ofclaim 1 wherein said substrate is

where R₁, R₂, R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloallcyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, thioester, ester, aldehyde and ketone.
 46. A compound ofclaim 45 where R₃, R₄, R₅, and R₆ are hydrogen atoms.
 47. A method forthe preparation of a compound of the formula:

according to claim 1, wherein two bromine atoms of an individualcyclobutane ring are in a trans orientation, according to the method ofclaim 1 wherein said substrate is

and where R₁, R₂, R₃, R₁, R₅, and R₆ are independently selected from agroup consisting of hydrogen, halogen, straight alkyl, branched alkyl,cycloalkyl, substituted alkyl, alkyl aryl, aryl, substituted aryl,heterocycle alkenyl, cycloalkenyl, ether, thioether, amide, amine,alcohol, nitro, tbioester, ester, aldehyde and ketone.
 48. A method ofclaim 47 where R₃, R₄, R₅, and R₆ are hydrogen atoms.
 49. A method forbromination comprising a. providing a substrate having an aromaticmoiety with at least one alkyl substituent; b. dissolving said substratein chloroform; c. introducing said substrate dissolved in said solvent,and a bromine source, to a reaction vessel, to form a reaction mixture;d. heating said reaction; and e. irradiating said reaction mixture withelectromagnetic radiation so as to effect the bromination of saidsubstrate.
 50. The method of claim 49 wherein said substrate has anaromatic moiety with at least two ortho alkyl substituents.
 51. Themethod of claim 49 wherein said electromagnetic radiation includescomponents having visible light wavelengths.
 52. The method of claim 49wherein said solvent includes at least 90% by weight of chloroform. 53.The method of claim 52 wherein said solvent includes at least 97% byweight of chloroform.
 54. The method of claim 53 wherein said solventcomprises substantially neat chloroform.
 55. The method of claim 49wherein said heating is to a boiling point of said solvent.
 56. Themethod of claim 49 wherein a starting concentration of said substrate insaid reaction solvent is between 0.01 M and 2 M.
 57. The method of claim49, wherein a starting concentration of said substrate in said reactionsolvent is between 0.01 M and 1 M.
 58. The method of claim 49, wherein astarting concentration of said substrate in said reaction solvent isbetween 0.01 M and 0.5 M.
 59. The method of claim 49, wherein a startingconcentration of said substrate in said reaction solvent is between 0.02M and 0.2 M.
 60. The method of claim 49, wherein a startingconcentration of said substrate in said reaction solvent is between 0.07M and 0.1 M.
 61. The method of claim 49 wherein at least one of said atleast one alkyl substituent is a methyl substituent.
 62. A method forthe preparation of a compound of the general formula:

according to the method of claim 49 wherein R₁ and R₂ are independentlyselected from a group consisting of hydrogen, halogen, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone; andwherein R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, fluorine, chlorine, iodine, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone. 63.The method of claim 62 where R₃, R₄, R₅, and R₆ are hydrogen atoms. 64.A method for the preparation of a compound of the general formula:

according to the method of claim 49 wherein R₁ and R₂ are independentlyselected from a group consisting of hydrogen, halogen, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, nitro, thioester, ester, aldehyde and ketone; andwherein R₃, R₄, R₅, and R₆ are independently selected from a groupconsisting of hydrogen, fluorine, chlorine, iodine, straight alkyl,branched alkyl, cycloalkyl, substituted alkyl, alkyl aryl, aryl,substituted aryl, heterocycle alkenyl, cycloalkenyl, ether, thioether,amide, amine, alcohol, intro, thioester, ester, aldehyde and ketone. 65.The method of claim 64 where R₃, R₄, R₅, and R₆ are hydrogen atoms. 66.The method of claim 1, wherein said reducing contact of the product withsaid mediator is selective with respect to said substrate.
 67. Themethod of claim 1, wherein said reducing contact of the product withsaid mediator is with respect to a contact of the product with saidmediator in an analogous batch reaction.
 68. The method of claim 20,wherein said extraction solvent is further selected so as to besubstantially immiscible with said reaction solvent.
 69. The method ofclaim 20, wherein said substrate is substantially insoluble in saidextraction solvent.